Production of omicron-(monoalkyl aminoalkyl) oximes of dibenzo-[a, d] cyclohepten-5-ones



United States Patent Ofiice 3,349,128 Patented Oct. 24, 1067 PRODUCTION OF O-(MONOALKYL AMINOALKYL) OXIMES F DIBENZO-[a,d] CYCLOHEPTEN-S- ONES Claude Ivan Judd, Mequon, Wis., assignor to Colgate- Palmoiive Company, New York, N.Y., a corporation of Delaware No Drawing. Filed Mar. 28, 1966, Ser. No. 537,677

1 Claim. (Cl. 260-566) ABSTRACT OF THE DISCLOSURE The compounds are aminoalkylated oximes of dibenzo [a,d]cyclohepten--ones which are useful as skeletal muscle relaxants, sedatives and antidepressants. A species disclosed as O- [fl- (N-methylamino ethyl] -10, 1 l-dihydrodibenzo[a,d1cyclo-hepten-5-one oxime fumarate. A method of preparing the named compound by hydrolytically cleaving the acyl group from the corresponding trifluoroacetamide derivative is disclosed.

I 1'OBAm and non-toxic physiologically acceptable acid addition salts in which Z may be either -CH=CH or X and Y represent hydrogen or one or more ring substituents such as a halogen, particularly chlorine, a lower alkyl containing from one to four carbon atoms such as methyl, ethyl, propyl or butyl, an S-lower alkyl containing from one to four carbon atoms such as thiomethyl, thioethyl, thiopropyl, thiobutyl, an O-lower alkyl containing from one to four carbon atoms such as methoxy, ethoxy, isopropyloxy, butyloxy and methylenedioxy and trifluoromethyl, B represents a straight or branched lower alkylene containing from one to eight carbon atoms such as methylene, ethylene and propylene, and Am represents an amino group such as wherein R and R may be hydrogen, a lower alkyl containing from one to four carbon atoms such as methyl, ethyl, propyl and butyl, phenyl and phenyl-lower alkyls such as benzyl, phenylethyl and cyclic amino groups such as piperazino, 4-lower alkyl piperazino, particularly 4- methyl piperazino, 4-hydroxy lower alkyl piperazino, particularly 4-hydroxy ethyl piperazino, pyrrolidino and piperidino.

The novel aminoalkylated oximes of dibenzo [a,d] cyclohepten-S-ones may be prepared by reacting a dibenzo[a,d] cyclohepten-S-one with hydroxylamine to form a dibenzo [a,d]cyclohepten-5-one oxime, forming an anion of the oxime by treating it with a base and reacting the oxime anion with an aminoalkyl ester such as an aminoalkyl halide or an aminoalkyl tosylate. This process can be represented as follows wherein X, Y, Z, B and Am have the significance previously assigned except that Am cannot represent a primary or secondary amino group such as when either or both of R or R are hydrogen, and wherein D is a halogen such as chlorine or bromine or a tosyloxy group.

Illustrative examples of some of the dibenzo[a,d]cyclohepten-S-ones which may be employed as starting materials in the process are:

Dibenzo a,d] cyclohepten-S -one,

10,1 l-dihydrodibenzo [a,d] cyclohepten-S-one,

3-chloro-10,1l-dihydrodibenzo[a,d]-cyclohepten-S-one,

7-methoxy-10,1 l-dihydrodibenzo [a,d] cyclohepten-S-one,

3 -ethyl-10,1 l-dihydrodibenzo [a,d] cyclohepten-S -one,

3,7-dichloro-10,1l-dihydrodibenzo[a,d]cyclohepten-5- one,

2,3,7,8-tetrachloro-10,1l-dihydrodibenzo[a,d]cyclohepten-S-one,

2-thiomethyl-10, 1 1-dihydrodibenzo[a,d] cyclohepten-S- one,

3-trifluoromethyl-10,1 l-dihydrodibenzo [a,d1cyclohept S-one,

3 ,7-dichlorodibenzo [a,d] cyclohepten-S-one, and

2,3-methylenedioxydibenzo [a,d] cyclohepten-S-one.

These dibenzo[a,d]cyclohepten-S-ones may be prepared in accordance with the process disclosed by A. C. Cope and S. W. Fenton in the Journal of the American Chemical Society, 73, 1673 (1951).

The oximes are prepared by treating the dibenzo[a,d] cyclohepten-S-ones with a hydroxylamine salt such as hydroxylamine hydrochloride in the presence of a suitable base such as pyridine, sodium acetate or sodium hydroxide. The reaction is readily efiected employing conventional conditions of solvent, temperature, and the like. A preferred procedure employs excess'base such as pyridine as an organic solvent and heating the mixture to reflux. A method for preparing 10,11-dihydrodibenzo[a,d]cyclohepten-S-one oxime is shown by Monro et al. in the Journal of Medicinal Chemistry, 6, 255-261 (1963).

The dibenzo[a,dJcyclohepten-S-one oximes are converted into their oxime anions by treating them with a base such as sodium hydride, sodamide, sodium hydroxide or potassium hydroxide. The oxime anion is then allowed to react with an aminoalkyl ester to form the final aminoalkyl-dibenzo[a,d]cyclohepten-S-one oximes. The reaction with the aminoalkyl ester is advisedly conducted in an organic reaction medium such as toluene. The reaction is promoted by the use of elevated temperatures, particularly advantageous is the reflux temperature. The reaction is generally completed in from one to four hours. The reaction mixture is then cooled and the product is isolated by conventional means such as by extracting with a solvent. These bases may be converted into their nontoxic physiologically acceptable acid addition salts. by treating the bases in the presence of an inorganic or organic acid such, as hydrochloric acid, maleic acid or fumaric acid.

Examples of the aminoalkyl esters which may be employed in this reaction are:

B-(N,N-dimethylamino) ethyl chloride. ,6-(N,N-dimethylamino)ethyl'tosylate, fi-(4-methyl-l-piperazinyl)ethyl chloride, fi-(4-hydroxyethyl-l-piperazinyl) ethyl bromide, B-(N benzyl-N-methylamino)ethyl chloride, fi-(N,N-dibenzylamino)propyl chloride, 'y-(N,N dimethylamino)propyl chloride,

18- l-pyrrolidyl ethyl chloride, 'y-(l-piperidynpropyl chloride.

Some of the aminoalkyl-dibenzo[a,d]cyclohepten-S-one oximes which may be prepared in this fashion are:

Compounds of this invention having a hydrogen on the amino-nitrogen may be prepared utilizing appropriate amino-protecting groups such as acyl, benzyl and carbobenzoxy which can be removed using standard techniques after the O-aminoalkyl chain has been added to the dibenzo [a,dlcyclohepten-S-one oxime.

A particularly desirable acyl blocking group is t,a,octrifluoroacetyl and the synthesis is accomplished by treating an appropriate oxime anion, prepared as previously described, with a N-haloloweralkyl-N-loweralkyl-a,egatrifluoroacetamide to form the trifiuoroacetamide derivative and then hydrolytically cleaving theacyl. group to prepare the corresponding secondary amine.

Some of the compounds which may be prepared in this fashion are The compounds of this invention which are unsymmetrical because of the placement of the ring substituents X and Y exist in isomeric forms known as syn and anti.

The aminoalkyl-dibenzo[a,d]cyclohepten-S-one oximes of this invention as well as their physiologically acceptable acid. addition salts are skeletal muscle relaxants and thus are useful in the control of skeletal muscle pain, lower back pain and muscle stiffness. The compounds of this invention also possess sedative and antidepressant.

activities.

The aminoalkyl-dibenzo[a,d] cyclohepten-S-one oximes disclosed in this application as well as their salts may be administered to animals and humans as pure compounds.

It is advisable, however, to first combine one or more of t the compounds with a suitable pharmaceuticalcarrier to attain a more satisfactory size to dosage relationship. Either liquid or solid pharmaceutical carriers may be employed. A preferred liquid carrier is water. However, other solvents such as propylene glycol may be employed. Additionally, flavoring materials may be added. The liquids may be administered either orally or parenterally.

Solid pharmaceutical carriers such as starch, sugar, talc and the like many be employed to form powders. The powders may be used as such for direct administration or, instead, they may be added to suitable foods and liquids including water to facilitate administration.

The powders may also be used to make tablets or to fill capsules. Suitable lubricants such as magnesium stearate, binders such as gelatin and disintegrating agents like sodium carbonate in combination with citric acid may be employed in the formation of tablets.

Unit dosage forms such as tablets and capsules may contain any suitable predetermined amount of one or more of the active agents described in this application and may be administered one or more at a time at regular intervals. Such unit dosage forms, however, should generally con tain a concentration of from 0.1% to 10% by weight of one or more of the active agents. Unit dosage forms should advisedly contain between 5 to mg. of the active agent. A typical tablet may have the following composition:

Powders (1), (2) and (3) are slugged, then granulated, mixed with (4) and (5) and tableted.

Capsules may be prepared by filling No. 3 hard gelatin capsules with the following ingredients:

Mg. (1) O-['y-(N,N-dimethylamino)propyl]-l0,11-

dihydrodibenzo[a,d]cyclohepten-5-one oxime fumarate 50 (2) Lactose U.S.P. 200 (3) Starch U.S.P. 16 (4) Talc U.S.P. 8

The-oral route, is generally preferred for administering the compounds of this invention. However, other routes of administration such as parenteral may be employed.

The following examples are presented to illustrate this invention.

EXAMPLE I N OH 10,] 1 -dihydr0dib enzo [a,d] cyclohepten-S-one oxime A mixture of 20.8 g. (0.1 mole) 10,11 dihydrodibenzo[a',d]cyclohepten-S-one, 20.8 g. (0.3 mole) hydroxylamine hydrochloride and 300 ml. pyridine are stirred at reflux for twenty-four hours. The mixture is evaporated under reduced pressure and suspended in water. The insoluble organic portions are extracted into ethyl ether and the ether is washed with five percent hydrochloric acid, five percent sodium bicarbonate and water. After drying over anhydrous potassium carbonate the solution is filtered and the filtrate evaporated under reduced pressure. The residues are triturated with Skelly B and the solids collected by filtration yielding the product, M.P. 163-166".

Analysis.-Calcd. for C H NO: N, 6.28. Found: N, 5.96.

EXAMPLE II NOH Dibenzo[a,d]cyclohepten-S-one oxime A mixture of 4.1 g. (0.02 mole) dibenzo[a,d]cyclohepten-S-one, 4.2 g. (0.06 mole) hydroxylamine hydrochloride and 75 ml. pyridine is heated under reflux for eighteen hours. The mixture is evaporated under reduced pressure, covered with ether and washed with 5% hydrochloric acid, 5% sodium hydroxide and water. The organic material is dried over anhydrous potassium carbonate, filtered and evaporated under reduced pressure. The residues are triturated under Skelly B and collected by filtration yielding the product, M.P. 184l85.

AnaZysis.-Calcd. for C H NO: C, 81.43; H, 5.01. Found: C, 81.38; H, 4.95. I

EXAMPLE III NOH 3-chZora-10,11-dihydr0dil1enz0 [a,d] cyclohepten-S-one oxime A mixture of 65.3 g. (0.27 mole) 3-chl0ro-10,l1-dihydrodibenzo[a,d]cyclohepten-S-one, 56.3 g. (0.81 mole) hydroxylamine hydrochloride and 800 ml. pyridine is stirred at reflux for 12 hours. The solvents are removed under reduced pressure and the residues are covered with one liter of ether and washed with 250 ml. portions of 3 N hydrochloric acid, 5% sodium hydroxide and water. The dried organic fraction is evaporated and the residues are triturated in Skelly B and collected by filtration, yielding the product. Further recrystallization from acetonitrile and Darco yields the product, M.P. 198201.

Analysis.--Calcd. for C H ClNO: C, 69.91; H, 4.70; N, 5.44; Cl, 13.76. Found: C, 69.91; H, 4.70; N, 5.34; Cl, 13.79.

EXAMPLE IV nooo-on u 1100 o H NOCzTLN Non.

O- [fl-(4-methyl-1-piperazinyl) ethyl] -10,11-a'ihydr0- dibenzo[a,d]cyclohepten-S-one Oxime An apueous solution of 16.8 g. (0.075 mole) 4-methyl- 1 piperazinylethylchloride dihydrochloride is covered with 100 ml. toluene and saturated with potassium carbonate. The aqueous fraction is washed repeatedly with toluene, the toluene fractions are combined, dried and filtered.

A mixture of 11.2 g. (0.05 mole) 10,11 dihydrodibenzo[a,d]cyclohepten-S-one oxime and 2.4 g. (0.05 mole) 50% sodium hydride in 100 ml. dry toluene is stirred at reflux for one hour, cooled to 25 C. and the above solution of 4-methyl-1-piperazinylethylchloride added and the mixture stirred at reflux for three hours. The cooled reaction miXt-ure is washed with water and the dried organic fraction evaporated under reduced pressure yielding a brown oil. The crude material (0.05 mole) and 11.6 g. (0.10 mole) maleic acid are warmed in sufficient ethanol to cause solution (150 ml.) and allowed to stand overnight. The solids which form on cooling are collected by 6 filtration yielding the product, M.P. 170172 C. Recry stallization from 1000 ml. hot ethanol yields the product, M.P. 174175 C.

Analysis.Calcd. for C H N O C, 61.95; H, 6.06; N, 7.24; N.E., 145.4. Found: C, 61.98; H, 6.25; N, 7.27; N.E., 146.0.

EXAMPLE V NO 0.11m HC-COOH CH3 Hooo i11 0- B- (N -benzy l-N -m'ethylamin0 ethyl 0,11-dihydr0dibenzo [a,d] cyclohepten-S-one oxime A solution of 13.25 g. (0.06 mole) N-benZyl-N-methylaminoethyl chloride hydrochloride in 50 ml. water, covered with 50 ml. toluene, is saturated with potassium carbonate. The aqueous fraction is washed repeatedly with toluene, the toluene fractions are combined, dried and filtered.

A mixture of 6.68 g. (0.03 mole) 10,11-dihydrodibenzo [a,d]cyclohepten-S one oxime and 1.4 g. (0.03 mole) 50% sodium hydride in 75 ml. dry toluene is stirred at reflux for one hour, cooled to 25 C. and the above solution of N-benzyl-N-methylaminoethyl chloride added and the mixture stirred at reflux for three hours. The cooled reaction mixture is washed with water and the dried organic fraction evaporated under reduced pressure yielding the crude product. The crude product (0.03 mole) and 3.48 g. (0.03 mole) fumaric acid are warmed in sufficient ethanol to cause solution (30 ml.), treated with Darco, filtered, diluted with 50 ml. ethyl ether and refrigerated. The solids which form on cooling are collected by filtration yielding the product, M.P. l28l31 C. Repeated recrystallization from isopropanol yields the pure product, M.P. 149-150 C.

Analysis.-Calcd. for C H N O C, 71.58; H, 6.21; N, 5.75. Found: C, 71.56; H, 6.15; N, 5.49.

EXAMPLE VI HC-C O OH 0H3 HO O C H l IO C3HQN/ 0- ['y- (N ,N -dim ethylam ino) pro pyl 0,1 1 -dihydro-dibenzo [a,d] cyclohepten-S-one oxime A mixture of 8.9 g. (0.04 mole) 10,11-dihydrodibenzo [a,d]cyclohepten-5-one oxime, 1.9 g. (0.04 mole) 50% sodium hydride and ml. dry toluene is stirred at reflux for one hour, cooled to 25 C. and 4.86 g. (0.04 mole) freshly distilled y-N,N-dimethylaminopropylchloride dissolved in 50 ml. dry toluene is added and the mixture stirred at reflux for three hours. The cooled reaction mixture is washed with water and the dried organic fraction evaporated under reduced pressure yielding a brown oil. The crude product (0.038 mole) and 4.45 g. (0.038 mole) fumaric acid was warmed in sufficient ethanol to cause solution, filtered and allowed to cool. The solids which form on cooling are collected by filtration yielding the product, M.P. 172179 C. A second crop of crystals is obtained by diluting the mother liquors to the cloud point with ethyl ether and collecting the solids which form by filtration. Recrystallization from 500 ml. hot isopropanol yields the pure product, M.P. 182-185 C.

Analysis.-Calcd. for C44H52H4O61 C, H, N, 7.64. Found: C, 71.73; H, 7.20; N, 7.33.

EXAMPLE v11 NO Cal-IrN HOOC- H B- (N -benzyl-N -methylamin0) ethyl -dibenz0 [1nd] cycl0hepten-5-one oxime A solution of 49.7 g. (0.226 mole) fl-(N-benzyl-N- methylamino)ethyl chloride hydrochloride in 100 ml. water, covered with 75 ml. toluene, is saturated with potassium carbonate. The aqueous fraction is washed repeatedly with toluene, the toluene fractions are combined, dried and filtered.

A mixture of 41.7 g. (0.188 mole) dibenzo[a,d]cyclohepten-S-one and 9.3 g. (0.188 mole) 50% sodium hydride in 400 ml. dry toluene is stirred at reflux for one hour, cooled to 20 C. and the above solution of B-(N-benzyl- N-methylarnino)ethyl chloride is added and the mixture is washed with water and the dried organic fraction evaporated under reduced pressure yielding a heavy brown oil. The crude product (0.152 mole) and 13.1 g. (0.152 mole). fumaric acid are warmed in suflicient ethanol to cause solution (400 ml.), filtered, diluted to the cloud point with ethyl ether, 400 ml. of acetonitrile are added and the mixture is refrigerated. The solids which form upon standing are collected by filtration yielding the product, M.P. 215- 220 C. Recrystallization from 750 ml. isopropanol and 200 ml. methanol to which a small amount offumaric acid is added yields the pure product, M.P. 215-222" C. Additional product is available from work-up of mother liquors.

Al1alySl S.CflICd. for C2gH23N205i C, N, 5.79. Found: C, 72.6; H, 6.3; N, 6.3.

EXAMPLE VIII Iii-430011 01 E00 o- H \\H/ CH3 O- [fi-(N,N-dimethylamino) ethyl] -3-chlor0-10,11-dihydr0dibenz0[a,d] cycloheptenJ-one oxime A mixture of 7.7 g. (0.03 mole) 3-chloro-10,1l-dihydrodibenzo[a,d]cyclohepten-5-one oxime and 1.4 g. (0.03 mole) 50% sodium hydride in 100 ml. dry toluene is stirredat reflux for one hour, cooled to 20 C. and 3.5 g. (0.03 mole) freshly distilled fl-dimethylaminoethyl chloride is added and the resulting mixture stirred at reflux for three hours. The cooled reaction mixture is washed with water and the dried organic fraction evaporated under reduced pressure yielding a dark brown oil. The crude product (0.029 mole) and 3.36 g. (0.029 mole) fumaric acid are warmed in suificient ethanol to cause solution (35 ml.), diluted with an equal volume of ethyl ether and the solids which form are collected by filtration yielding the product, M.P. 140143 C. The product is dissolved in 40 ml. hot isopropanol, treated with Darco, filtered and allowed to cool. The solids are collected by filtration yielding the pure product, M.P. l43144 C.

Analysis.Calcd. for C H ClN O C, 62.08; H, 5.66; Cl, 7.97; N, 63.30. Found: C, 62.25; H, 5.85; Cl, 7.96; N, 6.23.

EXAMPLE IX Cl HC-C O OH l loCzHiN NCH: 'HOOC H 0- [,6- (4-methyl-1-piperazinyl) ethyl] -3-chl0r0-l 0,1 1 -dihydrodib enzo [a,d] cyclohepten-S-one oxime A solution of 8.4 g. (0.037 mole) 4-methyl-1-piperazinyl ethyl chloride hydrochloride in 50 ml; water, covered with 50 m1. toluene, is saturated with potassium carbonate. The aqueous fraction is washed repeatedly with toluene, the toluene fractions are combined, dried and filtered.

A mixture of 6.4 g. (0.025 mole) 3-chloro-10,11-dihydrodibenzo[a,d]cyclohepten-S-one oxime and 1.2 g. (0.025 mole) 50% sodium hydride in ml. dry toluene is stirred at reflux for one hour, cooled to 25 C. and the above solution of 4-methyl-l-piperazinylethyl chloride is added and the'resulting mixture stirred at reflux for three hours. The cooled reaction mixture is washed with Water and the dried organic fraction evaporated under reduced pressure yielding a brown oil. The crude product (0.025 mole) and 5.8 g. (0.05 mole) fumaric acid are warmed in suflicient ethanol to dissolve (700 m1.), filtered and al-,

lowed to cool. The solids which form on cooling are collected by filtration yielding the product, M.P. -196 C. Recrystallization from 500 m1. hot ethanol yields the pure product, M.P. 195196 C.

Analysis.Calcd. for C H ClN O C, 62.45; H, 6.05; Cl, 7.09; N, 8.40. Found: C, 62.45; H, 6.14; CI, 7.01; N, 8.42.

EXAMPLE X NO CHzCIIzNHCH; 2

-HOOC-CH HG-COOH O- [fl-(N-methylamirzo) ethyl]-I0,1I-dihydrodibenzo [a,d] cyclohep ten-S-one oxime fumarate A mixture of 7.62 g. (0.034 mole) of 10,11-dihydrodibenzo[a,d] cyclohepten-S-one oxime, 1.3 g. (0.034 mole) of a 59% sodium hydride-oil dispersion and 200 ml. of dry toluene is refluxed for 1 hour. The mixture is cooled to 20 and a solution of the above amide (6.45 g., 0.034 mole) in 25 ml. of dry toluene is added dropwise. The mixture is refluxed overnight and cooled to room temperature. Water. (35 ml.) is added, the aqueous phase separated and the toluene removed from the organic layer. The residue is then stirred with a solution of 1.9 g. of potassium hydroxide in 100 ml. of ethanol for 60 hours. The ethanol is then distilled, the residue taken up in ether and this solution extracted with several portions of 6 N hydro-.

ll NO-B-N in which X and Y are hydrogen or halogen, Z is H=CH or -CH CH B is a lower a-lkylene, and R is lower alkyl, phenyl or phenyl-lower alkyl which comprises re action an anion of the formula ILIOS with a compound of the formula in which D is a reactive halide, B is lower alkylene, and R is a,a,a-trifluoroacetyl to form a compound of the formula R3 III and then hydrolytically cleaving said R to form a com- 0 pound of Formula I.

References Cited UNITED STATES PATENTS 25 2,832,804 4/1958 Richter et a1. 260-575 3,192,204 6/1965 Craig et a1. 260-240 3,270,055 8/ 1966 Engelhard et al 260-566 HENRY R. JILES, Primary Examiner. 

